The present invention relates to the use of prostaglandin E receptor agonists and partial agonists to stimulate mucin secretion to treat dry eye, keratoconjunctivitis, Sjogren""s syndrome and related ocular surface diseases.
Dry eye is a common ocular surface disease afflicting millions of people in the U.S. each year, especially the elderly (Schein et. al., Prevalence of dry eye among the elderly. American J. Ophthalmology, 124:723-738, (1997)). Dry eye may afflict an individual with varying severity. In mild cases, a patient may experience burning, a feeling of dryness, and persistent irritation such as is often caused by small bodies lodging between the eye lid and the eye surface. In severe cases, vision may be substantially impaired. Other diseases, such as Sjogren""s disease and cicatricial pemphigoid manifest dry eye complications.
Although it appears that dry eye may result from a number of unrelated pathogenic causes, the common end result is the breakdown of the tear film, which results in dehydration of the exposed outer surface of the eye. (Lemp, Report of the Nation Eye Institute/Industry Workshop on Clinical Trials in Dry Eyes, The CLAO Journal, 21(4):221-231 (1995)). Four events have been identified which singly or in combination are believed to result in the dry eye condition: a) decreased tear production or increased tear evaporation; b) decreased conjunctival goblet-cell density; c) increased corneal desquamation; and d) destabilization of the cornea-tear interface (Gilbard, Dry eye: pharmacological approaches, effects, and progress. The CLAO Journal, 22:141-145 (1996)). Another major problem is the decreased mucin production by the conjunctival cells and/or corneal epithelial cells of mucin, which protects and lubricates the ocular surface (Gipson and Inatomi, Mucin genes expressed by ocular surface epithelium Progress in Retinal and Eye Research, 16:81-98 (1997)).
Practitioners have taken several approaches to the treatment of dry eye. One common approach has been to supplement and stabilize the ocular tear film using so-called artificial tears instilled throughout the day. Another approach has been the use of ocular inserts that provide a tear substitute or to stimulate endogenous tear production.
Examples of the tear substitution approach include the use of buffered, isotonic saline solutions, aqueous solutions containing water soluble polymers that render the solutions more viscous and thus less easily shed by the eye. Tear reconstitution is also attempted by providing one or more components of the tear film such as phospholipids and oils. Examples of these treatment approaches are disclosed in U.S. Pat. No. 4,131,651 (Shah et. al.), U.S. Pat. No. 4,370,325 (Packman), U.S. Pat. No. 4,409,205 (Shively), U.S. Pat. No. 4,744,980 and U.S. Pat. No. 4,883,658 (Holly), U.S. Pat. No. 4,914,088 (Glonek), U.S. Pat. No. 5,075,104 (Gressel et. al.) and U.S. Pat. No. 5,294,607 (Glonek et. al.).
United States Patents directed to the use of ocular inserts in the treatment of dry eye include U.S. Pat. No. 3,991,759 (Urquhart). Other semi-solid therapy has included the administration of carrageenans (U.S. Pat. No. 5,403,841, Lang) which gel upon contact with naturally occurring tear film.
Another recent approach involves the provision of lubricating substances in lieu of artificial tears. U.S. Pat. No. 4,818,537 (Guo) discloses the use of a lubricating, liposome-based composition.
Aside from the above efforts, which are directed primarily to the alleviation of symptoms associated with dry eye, methods and compositions directed to treatment of the dry eye condition have also been pursued. For example, U.S. Pat. No. 5,041,434 (Lubkin) discloses the use of sex steroids, such as conjugated estrogens, to treat dry eye condition in post-menopausal women; U.S. Pat. No. 5,290,572 (MacKeen) discloses the use of finely divided calcium ion compositions to stimulate tear film; and U.S. Pat. No. 4,966,773 (Gressel et. al.) discloses the use of microfine particles of one or more retinoids for ocular tissue normalization.
Although these approaches have met with some success, problems in the treatment of dry eye nevertheless remain. The use of tear substitutes, while temporarily effective, generally requires repeated application over the course of a patient""s waking hours. It is not uncommon for a patient to have to apply artificial tear solution ten to twenty times over the course of the day. Such an undertaking is not only cumbersome and time consuming, but is also potentially very expensive.
The use of ocular inserts is also problematic. Aside from cost, they are often unwieldy and uncomfortable. Further, as foreign bodies introduced in the eye, they can be a source of contamination leading to infections. In situations where the insert does not itself produce and deliver a tear film, artificial tears must still be delivered on a regular and frequent basis.
In view of the foregoing, there is a clear need for an effective treatment for dry eye that is capable of alleviating symptoms, as well as treating the underlying physical and physiological deficiencies of dry eye, and that is both convenient and inexpensive to administer.
Mucins are proteins which are heavily glycosylated with glucosamine-based moieties. Mucins provide protective and lubricating effects to epithelial cells, especially those of mucosal membranes. Mucins have been shown to be secreted by vesicles and discharged on the surface of the conjuctival epithelium of human eyes (Greiner et. al., Mucus Secretory Vesicles in Conjunctival Epithelial Cells of Wearers of Contact Lenses, Archives of Ophthalmology, 98:1843-1846 (1980); and Dilly et. al., Surface Changes in the Anaesthetic Conjunctiva in Man, with Special Reference to the Production of Mucus from a Non-Goblet-Cell Source, British Journal of Ophthalmology, 65:833-842 (1981)). A number of human-derived mucins which reside in the apical and subapical corneal epithelium have been discovered and cloned (Watanabe et. al., Human Corneal and Conjuctival Epithelia Produce a Mucin-Like Glycoprotein for the Apical Surface, Investigative Ophthalmology and Visual Science (IOVS), 36(2):337-344 (1995)). Recently, a new mucin was reported to be secreted via the cornea apical and subapical cells as well as the conjunctival epithelium of the human eye (Watanabe et. al., IOVS, 36(2):337-344 (1995)). These mucins provide lubrication, and additionally attract and hold moisture and sebacious material for lubrication and the corneal refraction of light.
Mucins are also produced and secreted in other parts of the body including lung airway passages, and more specifically from goblet cells interspersed among tracheal/bronchial epithelial cells. Certain arachidonic acid metabolites have been shown to stimulate mucin production in these cells. Yanni reported the increased secretion of mucosal glycoproteins in rat lung by hydroxyeicosatetraenoic acid (xe2x80x9cHETExe2x80x9d) derivatives (Yanni et. al., Effect of Intravenously Administered Lipoxygenase Metabolites on Rat Trachael Mucous Gel Layer Thickness, International Archives of Allergy And Applied Immunology, 90:307-309 (1989)).
The conventional treatment for dry eye, as discussed above, includes administration of artificial tears to the eye several times a day. Other agents claimed for increasing ocular mucin and/or tear production include vasoactive intestinal polypeptide (Dartt et. al., Vasoactive intestinal peptide-stimulated glycocongjugate secretion from conjunctival goblet cells. Experimental Eve Research, 63:27-34, (1996)), gefarnate (Nakmura et. al., Gefarnate stimulates secretion of mucin-like glycoproteins by corneal epithelium in vitro and protects corneal epithelium from dessication in vivo, Experimental Eye Research, 65:569-574 (1997)), and the use of liposomes (U.S. Pat. No. 4,818,537), androgens (U.S. Pat. No. 5,620,921), melanocycte stimulating hormones (U.S. Pat. No. 4,868,154), phosphodiesterase inhibitors (U.S. Pat. No. 4,753,945), retinoids (U.S. Pat. No. 5,455,265) and hydroxyeicosatetraenoic acid derivatives (U.S. Pat. No. 5,696,166). However, many of these compounds or treatments suffer from a lack of specificity, efficacy and potency and none of these agents have been marketed so far as therapeutically useful products to treat dry eye and related ocular surface diseases. Thus, there remains a need for an efficacious therapy for the treatment of dry eye and related diseases.
Prostaglandins are metabolite derivatives of arachidonic acid. Arachidonic acid in the body is converted to prostaglandin G2, which is subsequently converted to prostaglandin H2. Other naturally occurring prostaglandins are derivatives of prostaglandin H2. A number of different types of prostaglandins are known in the art including A, B, C, D, E, F, G, I and J-Series prostaglandins (U.S. Pat. No. 5,151,444; EP 0 561 073 A1; Coleman et. al., VIII International Union of Pharmacology classification of prostanoid receptors: Properties, distribution, and structure of the receptors and their subtypes, Pharmacological Reviews, 45:205-229 (1994)). Depending on the number of double-bonds in the xcex1-(top chain) and/or the xcfx89-chain (bottom chain), the prostaglandins are further classified with subscripts such as PGD2, PGE1, PGE2, PGF2xcex1, etc. (U.S. Pat. No. 5,151,444; Coleman et. al., VIII International Union of Pharmacology classification of prostanoid receptors: Properties, distribution, and structure of the receptors and their subtypes, Pharmacological Reviews, 45:205-229 (1994)). Whilst these classes of prostaglandins interact preferably with the designated major classes of receptors (e.g. DP, EP, FP) and subclasses of receptors (e.g. EP2, EP3, EP4), the subscripts associated with the prostaglandin does not necessarily correspond with the subclass of the receptor(s) with which they interact. Furthermore, it is well known that these endogenous prostaglandins are non-specific in terms of interacting with the various classes of prostaglandin receptors. Thus, PGE2 not only interacts with EP2 receptors, but can also activate EP1, EP2, EP3 and EP4 receptors (Coleman et. al., VIII International Union of Pharmacology classification of prostanoid receptors: Properties, distribution, and structure of the receptors and their subtypes, Pharmacological Reviews, 45:205-229 (1994)).
In gastric mucosa, various prostaglandins known to be agonists at one or more of the prostaglandin E receptors have been shown to stimulate mucin secretion (Waterbury et. al., Stimulation of mucus production and prevention of aspirin induced ulcerogenesis by enprostil in the rat. Proc. West. Pharmacol. Soc., 31:21-3 (1988); Enss et. al., Effects of PGE2 and of different synthetic PGE derivatives on the glycosylation of pig gastric mucins. Prostaglandins, Leukotrienes, Essent. Fatty Acids, 59:49-54 (1998); Guslandi et. al., Gastric effects of a prostaglandin E1-derivative (Rioprostil) on acid, alkaline, and mucus secretion. Clin. Ther., 8:619-23. Katz et. al., Antigastrolesive, gastric antisecretory, diarrheagenic, and mucus-stimulating effects in rats following topically applied rioprostil, a synthetic prostaglandin E1 analog. Life Sci., 41:1591-8 (1987); Waterbury et. al., Stimulatory effect of enprostil, an anti-ulcer prostaglandin, on gastric mucus secretion. Am. J. Med., 81:30-3 (1986); Perkins et. al., Antisecretory, mucosal-protective, and diarrheagenic activity of a novel synthetic prostaglandin, SC-46275, in the rat. Drug Dev. Res., 23:349-58 (1991); Bunce et. al., GR63799Xxe2x80x94a novel prostanoid with selectivity for EP3 receptors. Adv. Prostaglandin. Thromboxane, Leukotriene Res. 21A:379-82 (1990); Sellers et. al., Misoprostol-induced increases in adherent gastric mucus thickness and luminal mucus output. Dig. Dis. Sci., 31:91S-95S (1986); Wilson et. al., Effects of misoprostol on gastric acid and mucus secretion in man. Dig. Dis. Sci., 31:126S-129S (1986)). Of interest in the present invention are prostaglandins which are believed to exhibit mucin-producing activity by binding to and activating any of the four recognized prostaglandin E receptors.
The present invention is directed to compositions and methods for the treatment of dry eye and other disorders requiring the wetting of the eye. More specifically, the present invention discloses compositions containing prostaglandin E receptor agonists and methods for treating dry eye type disorders.
Preferred compositions include an effective amount of a prostaglandin E receptor agonist for the production of mucins in mammals, and especially in humans. The compositions are administered topically to the eye for the treatment of dry eye.
It has now been discovered that certain prostaglandin E receptor agonists stimulate mucin production in human conjuctival epithelium and are therefore believed to be useful in treating dry eye. As used herein, the term xe2x80x9cprostaglandin E receptor agonistxe2x80x9d refers to any compound which acts as an agonist or partial agonist at one of the prostaglandin EP receptors (EP1, EP2, EP3, or EP4), thereby stimulating mucin production and/or secretion in the conjunctival epithelium and goblet cells following topical ocular application. Specifically included in such definition are compounds of the following formula I: 
wherein:
R1=(CH2)nCO2R, (CH2)nCONR4R5, (CH2)nCH2OR6, (CH2)nCH2NR7R8, where:
R=H or pharmaceutically acceptable cationic salt moiety, or CO2R forms a pharmaceutically acceptable ester moiety;
R4, R5=same or different=H, alkyl, or SO2CH3, with the proviso that if one of
R4, R5=SO2CH3, then the other=H or alkyl;
R6=H, acyl, or alkyl;
R7, R8=same or different=H, acyl, or alkyl; with the proviso that if one of
R7, R8=acyl, then the other=H or alkyl;
n=0 or 2;
----=single or double bond, which can be cumulated (i.e., carbons 4-6 can form an allene);
R9b=Cl, and R9a=H, or R9bR9a taken together=O as a carbonyl;
Y=CH2, O, or 
xe2x80x83where
R11=H, alkyl, or acyl;
A=O and B=CH2; or, Axe2x80x94B=CH2CH2 or cis-CHxe2x95x90CH; with the proviso that Axe2x89xa0O when Y=O.
one of C, D=H, and the other=CH3 or OR2, where R2=H, acyl, or alkyl; or C=D=H;
E and F=same or different=H or CH3; or one of E, F=CH3 and the other=OR2, where R2 is defined as above; with the proviso that exactly one of C, D, E, and F=OR2;
X=O or direct bond;
R20=C2-8 alkyl, C2-8 alkenyl, aryl, heteroaryl, aryloxy, or heteroaryloxy, optionally substituted with halo, trihalomethyl, OR3, NR3R21, wherein R3=H, alkyl, or acyl; and R21=H, alkyl, or acyl; with the proviso that if one of R3 and R21=acyl, then the other=H or alkyl: and wherein the C2-8 alkyl and C2-8 alkenyl may be optionally terminated by C3-8 cycloalkyl, C4-8 cycloalkenyl, aryl, heteroaryl, aryloxy, or heteroaryloxy, optionally substituted as described above; with the proviso that R20xe2x89xa0aryloxy or heteroaryloxy when X=O;
with the proviso that the following compounds of formula I be excluded:
those wherein all of the following limitations are satisfied:
----=a single bond between carbons 4 and 5 and a single or double bond between carbons 5 and 6;
R9aR9b=O as a carbonyl;
Y=CH2 or 
xe2x80x83where
R11 as defined above;
Axe2x80x94B=CH2CH2 or CHxe2x95x90CH;
one of C, D=H and the other=OR2, where R2 is as defined above; and
E and F=same or different=H or CH3.
Included within the scope of the present invention are the individual enantiomers of the title compounds, as well as their racemic and non-racemic mixtures. The individual enantiomers can be enantioselectively synthesized from the appropriate enantiomerically pure or enriched starting material by means such as those described below. Alternatively, they may be enantioselectively synthesized from racemic/non-racemic or achiral starting materials. (Asymmetric Synthesis; J. D. Morrison and J. W. Scott, Eds.; Academic Press Publishers: New York, 1983-1985, volumes 1-5; Principles of Asymmetric Synthesis; R. E. Gawley and J. Aube, Eds.; Elsevier Publishers: Amsterdam, 1996). They may also be isolated from racemic and non-racemic mixtures by a number of known methods, e.g. by purification of a sample by chiral HPLC (A Practical Guide to Chiral Separations by HPLC; G. Subramanian, Ed.; VCH Publishers: New York, 1994; Chiral Separations by HPLC; A. M. Krstulovic, Ed.; Ellis Horwood Ltd. Publishers, 1989), or by enantioselective hydrolysis of a carboxylic acid ester sample by an enzyme (Ohno, M.; Otsuka, M. Organic Reactions. volume 37, page 1 (1989)). Those skilled in the art will appreciate that racemic and non-racemic mixtures may be obtained by several means, including without limitation, nonenantioselective synthesis, partial resolution, or even mixing samples having different enantiomeric ratios. Departures may be made from such details within the scope of the accompanying claims without departing from the principles of the invention and without sacrificing its advantages. Also included within the scope of the present invention are the individual isomers of the disclosed compounds substantially free of their respective enantiomers.